rs4149339

Positions:

• chr9-104782875-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005502.4(ABCA1):​c.*1440C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 149,952 control chromosomes in the GnomAD database, including 8,824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8810 hom., cov: 30)
  • Exomes 𝑓: 0.31 (14 hom.)
• Consequence: ABCA1 NM_005502.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.73

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

NIPSNAP3B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 9-104782875-G-A is Benign according to our data. Variant chr9-104782875-G-A is described in ClinVar as [Benign]. Clinvar id is 364351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.*1440C>T		3_prime_UTR_variant	50/50	ENST00000374736.8	NP_005493.2
NIPSNAP3B	XR_007061325.1	n.960-4742G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736	c.*1440C>T		3_prime_UTR_variant	50/50	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995	c.*1440C>T		3_prime_UTR_variant	50/50			ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.330 AC: 49275 AN: 149466 Hom.: 8791 Cov.: 30

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.310

GnomAD4 exome AF: 0.306 AC: 125 AN: 408 Hom.: 14 Cov.: 0 AF XY: 0.268 AC XY: 66 AN XY: 246

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.330 AC: 49331 AN: 149544 Hom.: 8810 Cov.: 30 AF XY: 0.333 AC XY: 24207 AN XY: 72730

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.382

Gnomad4 ASJ AF: 0.185

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.292

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.317

Alfa AF: 0.286 Hom.: 13452

Bravo AF: 0.340

Asia WGS AF: 0.572 AC: 1984 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tangier disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypoalphalipoproteinemia, primary, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.083
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4149339; hg19: chr9-107545156;